ISOLATION AND CHARACTERIZATION OF MUTATIONS IN THE HUMAN HOLOCARBOXYLASE SYNTHETASE CDNA

Holocarboxylase synthetase (HCS) plays an essential role in biotin uti lization in eukaryotic cells and its deficiency causes biotin-responsi ve multiple carboxylase deficiency in humans. We have cloned the human HCS cDNA and show that antiserum against the recombinant protein immu noprecipitates human HCS. A one base deletion resulting in a premature termination and a missense mutation (Leu to Pro) were found in cells from siblings with HCS deficiency. Human HCS shows homology to BirA, w hich acts as both a biotin-[acetyl-CoA-carboxylase] ligase and a bioti n repressor in E. coli, suggesting a functional relationship between t he two proteins. The human HCS gene maps to chromosome 21q22.1.